RT Journal Article
SR Electronic
T1 Pharmacological Inhibition of Platelet-tumor Cell Cross-talk Prevents Platelet-induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.084988
DO 10.1124/mol.113.084988
A1 Melania Dovizio
A1 Thorsten J. Maier
A1 Sara Alberti
A1 Luigia Di Francesco
A1 Emanuela Marcantoni
A1 Gotz Munch
A1 Costance M. John
A1 Beatrix Suess
A1 Alessandro Sgambato
A1 Dieter Steinhilber
A1 Paola Patrignani
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/04/11/mol.113.084988.abstract
AB Cyclooxygenase(COX)-2-derived prostanoids can influence several processes that are linked to carcinogenesis. We aimed to address the hypothesis that platelets contribute to aberrant COX-2 expression in HT29 colon carcinoma cells and to reveal the role of platelet-induced COX-2 on the expression of proteins involved in malignancy and marker genes of epithelial-mesenchymal transition(EMT). Human platelets co-cultured with HT29 cells rapidly adhered to cancer cells and induced COX-2 mRNA expression, but not protein synthesis which required the late release of platelet PDGF and COX-2 mRNA stabilization. Platelet-induced COX-2-dependent PGE2 synthesis in HT29 cells was involved in downregulation of p21WAF1/CIP1 and upregulation of cyclinB1, since these effects were prevented by rofecoxib(a selective COX-2 inhibitor) and rescued by exogenous PGE2. Galectin-3, highly expressed in HT29 cells, is unique among galectins because it contains a collagen-like domain. Thus, we studied the role of galectin-3 and platelet collagen receptors in platelet-induced COX-2 overexpression. Inhibitors of galectin-3 function(β-lactose, a dominant-negative form of galectin-3,Gal-3C, and anti-galectin-3 antibody M3/38) or collagen receptor-mediated platelet adhesion(revacept, a dimeric collagen receptor GPVI-Fc) prevented aberrant COX-2 expression. Inhibition of platelet-cancer cell interaction by revacept was more effective than rofecoxib in preventing platelet-induced mRNA changes of EMT markers suggesting that direct cell-cell contact and aberrant COX-2 expression synergistically induced gene expression modifications associated with EMT. In conclusion, our findings provide the rationale for testing blockers of collagen binding sites, such as revacept, and galectin-3 inhibitors in the prevention of colon cancer metastasis in animal models followed by studies in patients.